Plasma cell disorders: Pathology review

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Case Study0:00–0:45

At the family medicine department, a 70 year old male named Ian came in with progressive fatigue and chronic back pain. His lab tests show anemia with an MCV of 90.
as well as increased calcium, blood urea nitrogen and creatinine levels. Peripheral blood smear showed the following.
Next to Ian, there’s a 65 year old female named Amanda that complains of progressive fatigue, recurrent nosebleeds and blurred vision.
Clinical examination reveals palpable liver and spleen. Her lab tests show anemia with normal MCV, reticulocyte count index over 2%, increased LDH, and a positive Coombs test.
Although their symptoms are very different, both Ian and Amanda have a plasma cell disorder. Plasma cell disorders are a group of hematological malignancies that are characterized by unregulated proliferation of plasma cells in the bone marrow.

Pathology0:45–1:22

They include multiple myeloma, monoclonal gammopathy of unknown significance or MGUS(em-gus), and Waldenström’s macroglobulinemia.
Each of them produce a monoclonal or M-protein, which is a unique protein of a single type, like a protein “clone”. Because plasma cells normally make immunoglobulins, it’s not surprising that the M-proteins produced are also immunoglobulins Alright, now let’s take a closer look at these different plasma cell disorders, starting with multiple myeloma, which is the most common primary bone tumor in people older than 40 to 50 years of age.

Multiple Myeloma 1:22–5:56

In multiple myeloma, the most common M-protein produced is IgG, followed by IgA, and these immunoglobulins have both a heavy and light chain.
More rarely, the myeloma cells can only make the kappa or lambda light chain of the immunoglobulin, and in that situation, the resulting protein is called the Bence-Jones protein.
A high yield concept is the clinical presentation of multiple myeloma, which can be summarized with the mnemonic CRAB (like the animal), “C” is for hypercalcemia, which results from increased osteoclast activity due to the release of osteoclast activating factor from the malignant plasma cells, which resorbs the bone and releases free calcium into the circulation.
Remember that your exam might not just give you the lab finding, but instead give you some symptoms of hypercalcemia, such as abdominal pain, psychiatric changes, constipation or fatigue.
Okay, “R” is for renal disease, which can be caused by multiple mechanisms. First, the light chains can deposit in and obstruct the renal tubules, and this is called light chain cast nephropathy, or myeloma kidney.
Renal disease can also be due to type two renal tubular acidosis, or even hypercalcemia which may cause the formation of calcium phosphate kidney stones.
Now, multiple myeloma can also lead to a specific type of amyloidosis called primary amyloidosis. Here, the immunoglobulin light chains leave the circulation and abnormally aggregate in various tissues, resulting in various clinical manifestations These include restrictive cardiomyopathy, a large tongue, also called macroglossia, and nephrotic syndrome to name a few.
So on the exam, beware of primary amyloidosis being a presenting feature of multiple myeloma. “A” is for anemia, which causes fatigue and shortness of breath.
The anemia occurs because the malignant cells infiltrate the bone marrow, and disrupt the normal production of red blood cells.
Finally, “B” is for bone pain, which is due to increased osteoclast activity causing pathologic fractures and lytic bone lesions.
So, in the exams, look for an elderly individual with symptoms of anemia and chronic back pain. Other manifestations include spinal cord compression if the tumor infiltrates from the vertebrae, and frequent infections, because although the tumor is making lots of immunoglobulins, they are not functional immunoglobulins and so they are not useful in fighting infections.
So for the test remember that a workup for multiple myeloma includes a CBC, which often shows normocytic normochromic anemia, and a peripheral smear, which can show a rouleaux formation due to IgG proteins attaching to red blood cell membranes, and then connecting with other red blood cell membranes, making the red blood cells stick to one other, causing them to look like a stack of coins.
Serum and urine protein electrophoresis, or SPEP(es-pep) and UPEP(you-pep), respectively, are important to see which M protein is predominantly being produced, and is seen as an M-spike.
SPEP detects most multiple myeloma patients that predominantly make IgG, followed by IgA, while UPEP is used to detect the minority of multiple myeloma patients, who only make the Bence-Jones protein.
UPEP is needed because these light chains are rapidly filtered from the blood, so they may not be seen on SPEP. A urine dipstick is not sufficient, as it only detects albumin.
Also beta-2 microglobulin, a component of the major histocompatibility class 1 antigens found on all nucleated cells, can be shed in the serum.
Serum levels of beta-2 microglobulin are checked in multiple myeloma, because the higher they are, the more severe the disease.
Then, a skeletal radiographic survey should be done to look for “punched out” lytic lesions. A bone scan should not be obtained, as it only detects osteoblastic lesions, not osteolytic lesions.
Finally, another high yield fact is that a bone marrow aspiration and biopsy must be obtained, to look for more than 10% plasma cells which infiltrate into the bone marrow.
Remember that plasma cells tend to have a “fried egg” appearance where the large nucleus located at the edge of the cell is the yolk, and the cytoplasm is the egg white.
In the cytoplasm, you might see immunoglobulin inclusion bodies. Now if we zoom in on the nucleus, we can see another distinguishing feature called clock-face nuclei where the chromatin forms a ring, like the numbers on a clock.
Moving on, monoclonal gammopathy of undetermined significance, or MGUS, is a premalignant plasma cell disorder that makes an M-protein which is usually IgG, so calling it “monoclonal gammopathy” makes sense.

MGUS5:56–6:41

There’s about a 1% per year risk of progression to multiple myeloma or another malignancy, so that’s why there’s the term “undetermined significance”.
Okay, now, unlike multiple myeloma, MGUS doesn’t present with CRAB findings and it’s completely asymptomatic. Also, patients have an SPEP positive for IgG, so you might instinctively think it’s multiple myeloma!
But, the difference is that MGUS is completely asymptomatic, the skeletal survey is negative, and a bone marrow biopsy will show less than 10% plasma cells.
Finally, Waldenström’s macroglobulinemia is unique because it’s actually a rare type of B-cell lymphoma called lymphoplasmacytic lymphoma, but since the cells secrete the M-protein IgM, it’s classified as a plasma cell disorder.

Waldenstrom Macroglobuli6:41–8:08

To help you remember this, “macroglobulinemia” literally means “large protein”, and IgM is the largest of the immunoglobulins.
Although it’s commonly asymptomatic, the symptoms that do occur are mainly attributed to hyperviscosity syndrome, which leads to mucosal bleeding from the nose and gums.
In the eyes, distension of retinal veins causes retinopathy or blurring and loss of vision. Raynaud phenomon is another common symptom where the tips of the fingers turn blue or white when exposed to cold.
IgMs can also inappropriately act as autoantibodies against red blood cells, causing autoimmune hemolytic anemia which typically presents with fatigue and general weakness.
Autoantibodies can also attack the sheaths of nerves, causing peripheral neuropathy. Lastly, the immunoglobulins tend to accumulate in the lymph nodes, spleen and liver, making these organs enlarge, and causing lymphadenopathy, splenomegaly, and hepatomegaly, respectively.
Finally, the SPEP will be positive for IgM, and similar to MGUS, the skeletal survey will often be negative. But, unlike MGUS, bone marrow biopsy will show more than 10% lymphoplasmacytic cells.
All right, as a quick recap, Plasma cell disorders are a group of bone marrow neoplasms that make characteristic monoclonal proteins.

Review8:08–9:05

They include multiple myeloma, which usually makes IgG, monoclonal gammopathy of undetermined significance, or MGUS, which also usually makes IgG, and Waldenström’s macroglobulinemia, which usually makes IgM.
Multiple myeloma patients present with CRAB symptoms, which are hypercalcemia, renal disease, anemia, and bone pain. A skeletal survey shows lytic bone lesions and a bone marrow biopsy reveals more than 10% plasma cells.
MGUS, on the other hand, is usually asymptomatic, has no bone lesions, and a bone marrow biopsy shows less than 10% plasma cells.
Waldenström’s macroglobulinemia patients can have hyperviscosity syndrome or autoimmune hemolytic anemia. A bone marrow biopsy often shows more than 10% lymphoplasmacytic cells.
Now, back to the patients! Due to his age and the presence of normocytic anemia, bone pain, hypercalcemia, and renal insufficiency, which are all CRAB findings, Ian most likely has multiple myeloma.

Summary9:05–10:01

Rouleaux formation on peripheral blood smear is also a clue for multiple myeloma. SPEP and UPEP will be sent to see which M protein is predominantly being produced and a skeletal radiographic survey should be done to look for “punched out” lytic lesions.
To confirm the diagnosis a bone marrow aspiration and biopsy must be obtained, to look for more than 10% plasma cells which infiltrate into the bone marrow.
Now, Amanda has symptoms of hyperviscosity such as nosebleeds and blurred vision, hepatosplenomegaly, and autoimmune hemolytic anemia.
So, she most likely has Waldenstrom’s macroglobulinemia. To confirm the diagnosis, SPEP must be positive for IgM and bone marrow biopsy will show more than 10% plasma cells.